Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2[N:20](COCC[Si](C)(C)C)[N:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:20][N:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:26][CH2:25]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(F)ccc3c21
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 8 %

Procedure:
A round-bottomed flask equipped with a septum having a top-mounted argon intake is charged with 95 mg of 5-(2,6-difluorophenyl)-7-fluoro-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}1-([2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline in 10 ml of DCM. After cooling to 0° C. using an ice bath, 0.173 ml of TFA are added and the mixture is stirred at RT for 20 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of water and 2 ml of 0.75M aqueous ammonia solution. The product is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. It is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (95/05 by vol.), to give 6 mg of 5-(2,6-difluorophenyl)-7-fluoro-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline (yellow solid). MS (E/I): m/z=475 (M+); 1H NMR: 1.67 (m, 2 H) 2.10 (m, 2 H) 2.87 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.79 (m, 1H) 6.08 (d, J=8.3 Hz, 1 H) 7.29 (m, 1 H) 7.33 (t, J=7.8 Hz, 2 H) 7.68 (m, 1 H) 7.88 (broad t, J=9.3 Hz, 1 H) 8.50 (dd, J=9.3, 5.4 Hz, 1 H) 12.80 (s, 1 H)*.
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:33]([O-])=O)[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5]>CC(C)=O.[Zn]>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:33])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
Ammonium chloride (4.10 g, 76.6 mmol) and water (9.1 mL) were added to a solution of 1-[6-nitro-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (5.92 g, 85% pure, 10.9 mmol) in acetone (46 mL). Zinc dust (5.01 g, 76.6 mmol) was then added in portions with vigorous stirring. Stirring was continued for 45 min, at which point the reaction mixture was filtered through diatomaceous earth. The filter cake was rinsed thoroughly with EtOAc (100 mL). The filtrate was concentrated and the residue was dissolved in EtOAc (75 mL), decanting from the remaining salts. The organic layer was washed with brine (45 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (2-70% EtOAc/hexanes) to yield the titled compound (4.19 g, 89% yield). MS (ESI/Cl): mass calcd. for C20H27N5O4Si, 430.2; m/z found, 429.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (d, J=0.6 Hz, 1H), 8.15 (d, J=0.6 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.6, 2.8 Hz, 1H), 5.78 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.09 (s, 2H), 3.57-3.43 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 0.86-0.74 (m, 2H), -0.08 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[C:22](=[O:25])(O)[O-:23].[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:22](=[O:25])[O:23][C:4]([CH3:15])([CH3:5])[CH3:3])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-Bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (2.31 g, 4.87 mmol, prepared as described in Method BB26) was dissolved in dioxane (24.36 mL). 25 mL of saturated sodium bicarbonate solution was added, followed by boc-anhydride (11.31 mL, 48.7 mmol). The reaction was stirred overnight at RT. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography on silica gel (0-25% EtOAc:Hex) to afford (S)-tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (2.614 g, 4.55 mmol) as a yellow solid. MS m/z=597.9 [M+H]+. Calculated for C19H17BrIN3O3S: 574.23.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:28](OC(=O)C)(=[O:30])[CH3:29]>O.C(OCC)(=O)C>[C:28]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:12][C:13]2[CH:20]=[CH:19][C:16]([CH3:17])=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(C(=Cc2ccc(C)cc2)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
To a mixture of (4-hydroxyphenyl)-acetic acid (18.3 g, 120.3 mmol) and 4-methylbenzaldehyde (12.0 g, 100 mmol) in 250 mL acetic anhydride was added potassium carbonate (11.9 g, 121.2 mmol). The reaction mixture was stirred at 80° C. for 16 h before it was cooled to room temperature. To the mixture was added 100 mL H2O, 5% HCl in water to pH 1 and 200 mL ethyl acetate. The mixture was then heated to 80° C. until all ethyl acetate was evaporated. The precipitate was filtered and washed with water and hexane. The filter cake was recrystallized out of toluene, filtered, washed with hexane and dried under vacuum to yield a pale yellow powder (20.16 g, 68.1%). 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.74 (s, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 2.29 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].O.[OH-].[Li+]>CS(C)=O>[CH:7]([N:5]1[N:4]=[C:3]([C:10]#[N:11])[C:2]([NH:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[N:6]1)([CH3:9])[CH3:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)n1nc(N)c(C#N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)n1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])n1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Combine 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g, 0.292 mol) and 2-fluoronitrobenzene (41.25 g, 0.292 mol) in dimethylsulphoxide (590 ml) and stir in the presence of lithium hydroxide monohydrate (24.56 g;0.584 mol) for eighteen hours at 55° C. Pour the reaction mixture onto ice-water, stir for one hour, filter and wash the filter pad well with water to leave a yellow crystalline solid to give 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole4-carbonitrile (73.7 g, 93% yield): 1HNMR/c: 1.6 ppm (d, 6H), 4.8 ppm (m, 1H), 7.05 ppm (tr, 1H), 7.64 ppm (tr, 1H), 8.2 ppm (dd, 1H), 8.28 ppm (dd, 1H), 10.25 ppm (s, 1H).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)=[O:10].C=O.[CH3:33]CCCCC.CCOC(C)=O>CC(O)=O>[CH3:33][N:2]([CH3:1])[C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)=[O:10]
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4cccc(N)c4)cc3)sc2c1
Reactant: [BH3-]C#N
Reactant: CCCCCC
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4cccc(N(C)C)c4)cc3)sc2c1
Yield: 28 %

Procedure:
Prepared as described in the Amination section using sodium cyanoborohydride (0.44 g, 6.95 mmol), 3-amino-N-[4-(6-methyl benzothiazol-2-yl)-phenyl]-benzamide (0.50 g, 1.39 mmol) and paraformaldehyde (0.42 g, 13.9 mmol) in AcOH (8 ml) to give the title compound (0.15 g, 28%) as a colourless solid after work-up and flash chromatography (2:1 Hexane/EtOAc).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[C:7]([Cl:16])[CH:6]=1)=[O:4].[CH:17]([NH:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[S:22])([CH3:19])[CH3:18]>>[ClH:1].[Cl:16][C:7]1[CH:6]=[C:5]([C:3]2([OH:4])[CH2:2][S:22][C:21](=[N:20][CH:17]([CH3:19])[CH3:18])[N:23]2[CH:24]([CH3:26])[CH3:25])[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]=1[Cl:15]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)cc(Cl)c1Cl
Reactant: CC(C)NC(=S)NC(C)C
Product: CC(C)N=C1SCC(O)(c2cc(Cl)c(Cl)c(S(N)(=O)=O)c2)N1C(C)C
Product: Cl

Procedure:
was obtained in a manner analogous to the method described in Example 1 d from 6.1 g of 2,3',4'-trichloro-5'-sulfamoylacetophenone and 1,3-diisopropyl-thiourea. M.p. 171° C (decomposition).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([OH:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[CH:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCC=O
Temperature: 15 °C

Procedure:
A solution of oxalylchloride (8.0 mL, 88.0 mmol, 2.2 eq.) in abs. dichloromethane (200 mL) was treated with DMSO (13.6 mL, 192 mmol, 4.8 eq.) at −60° C. After 3 min the reaction mixture was warmed to approx. 15° C. Then a solution of tetradecan-1-ol (8.56 g, 40.0 mmol) in dry dichloromethane (40 mL) and after further 3 min triethylamine (28 mL, 200 mmol, 5.0 eq.) were added. Then the reaction mixture was slowly warmed to 5° C. and quenched by addition of water (200 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic phases were washed with brine (1×200 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the product was isolated as a white solid, which was used in the next reaction without purification. Yield: 10.4 g (100%), purity: 98% (GC).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:16][C:17]([O:19][CH2:20][CH2:21][C:22]#[N:23])=[O:18])(=O)[CH2:13][CH3:14].N1CCCCC1.C(O)(=[O:32])C>CC(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:12]([C:13](=[O:32])[CH3:14])[CH2:16][C:17]([O:19][CH2:20][CH2:21][C:22]#[N:23])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)CC(=O)OCCC#N
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)CC(=O)OCCC#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate (17.0 g, 0.1005 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 24 h. The white solid, 2-cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate, formed was filtered, washed with 2-propanol (2×50 mL) and dried (28.34 g, 97%); m.p. 98-100° C.
Reaction SMILES: [OH-].[K+].[CH2:3]1OCCOCCOCCOCCOCCOC1.[C:21]([C:25]1[CH:29]=[CH:28][CH2:27][C:26]=1C)([CH3:24])([CH3:23])[CH3:22].[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)[CH3:32].Cl>C1COCC1>[C:21]([C:25]1[CH:26]=[C:27]([CH3:28])[C:32](=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:3])[CH:29]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC(=O)c1ccccc1
Reactant: CC1=C(C(C)(C)C)C=CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=CC(C(C)(C)C)=CC1=C(C)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a 100-ml three-neck flask, 1.50 g of potassium hydroxide pulverized in mortar, 0.91 g of 18-crown-6 and 45 ml of THF were charged under nitrogen atmosphere. 2.70 g of t-butyl-methylcyclopentadiene was added dropwise thereto over 10 minutes in a water bath, and the mixture was stirred for 3 hours. The solution was added with 11.33 g of acetophenone dropwise over 10 minutes, and the mixture was stirred for 22 hours. The reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with 200 ml of hexane. The separated organic layers were combined, and washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and a saturated aqueous solution of sodium chloride. After the solution was dried over magnesium sulfate, the solvent was distilled off, and the obtained product was purified by column chromatography. The yield was 1.98 g. Identification was performed by 1H-NMR spectrum. The measurement result is shown as follows. The result of the 1H-NMR spectrum proved that the obtained compounds are a mixture of the isomers.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1)=O>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: Cn1cc(C(=O)O)cc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Br)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-bromo-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:27])[CH:13]([OH:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:27])[CH:13]([O:26][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: COc1cc(C(O)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(2,2-dimethyl-2H-chromen-6-yl)-2-hydroxy-2-(3,4,5-trimethoxy-phenyl)-ethanone (28 mg, 0.073 mmol) in dichloromethane (1.5 mL) is added p-toluenesulfonyl chloride (15.3 mg, 0.080 mmol) and pyridine (6.47 μL, 0.080 mmol). The reaction mixture continues to stir at room temperature. The crude material is purified using silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[CH2:23](I)[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH2:23][CH3:24])=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O

Procedure:
A 59.7 g portion of the above ester was suspended in 425 ml of dimethylformamide, 76.6 g of pctassium carbonate was added and this mixture was stirred in an oil bath at 80°-90° C. An 89 ml portion of ethyl iodide was added, the mixture was stirred at 80°-90° C. for 18 hours and then evaporated. The residue was dissolved in water and then extracted with dichloromethane. The extract was washed with water, dried, filtered through hydrous magnesium silicate and evaporated in vacuo. The solid was recrystallized from ethanol, giving 38 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH3:32])[CH:39]=2)[CH:24]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2cc(F)ccc2OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 82.6 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 3-methoxyphenylboronic acid (28 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (44 mg, 83%). MS m/e 437.29 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]([O-])=O.[Na+]>O.CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[N:10][NH:9][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2nn[nH]c2c1
Yield: 137.7 %

Procedure:
The mixture of 4-bromobenzene-1,2-diamine (200 mg, 1.1 mmol) and NaNO2 (569 mg, 5.3 mmol) in H2O/AcOH (5 mL/50 mL) was reacted at 80° C. for 6 hours. The mixture was concentrated, the residue was dissolved in DCM and extracted with water, and the organic phase dried by Na2SO4 and concentrated to give 300 mg of crude product which was used without further purification. LCMS (m/z): 198.1/199.1 [M+H]+/[M+2H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5](Cl)=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)=[N:4][C:3]=1[CH3:13]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(C)c1Br
Product: Cc1nc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c(C)c1Br

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-bromo-6-chloro-2,4-dimethyl-5-nitropyridine (step 2) and 4-aminophenylethyl alcohol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[H][H].[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C@H:24]1[CH2:29][CH2:28][C@H:27]([CH:30]=O)[CH2:26][CH2:25]1>O.C(COC)OC>[CH3:3][O:4][C:5]([CH:7]=[CH:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=2[F:16])[CH2:29][CH2:28]1)=[O:6]
Reactant: O=C[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C=C[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 2 g of 60% sodium hydride and 80 ml of dimethoxyethane were placed in a 200 ml flask whose content was replaced with argon. Then, 9.1 g of trimethyl phosphonoacetate was added dropwise to the reaction mixture under ice water cooling. The resultant reaction mixture was allowed to warm to room temperature and stirred until the generation of hydrogen stopped. Then, 11.2 g of trans-4-(2,3-difluorophenyl)cyclohexanecarbaldehyde was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, a solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=3/1 to toluene) to obtain 13.6 g of 1-[trans-4-(2-methoxycarbonylvinyl)cyclohexyl]-2,3-difluorobenzene (Y: 97.0%). The compound thus obtained had a purity of 96% (mixture of E and Z isomers).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][N:22]=[C:23]=[S:24]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[S:24])[N:8]=1
Reactant: NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine in warm acetonitrile (15 ml.) was allowed to cool to room temperature. A solution of methylisothiocyanate (0.15 g.) in acetonitrile (1 ml.) was added and the mixture stirred overnight. Evaporation to dryness gave a yellow solid which was recrystallised from a small volume of ethyl acetate to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[3-(3-methylthioureido)propylthio]pyrazine (0.32 g.), m.p. 165°-167°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][N:16]([CH2:2][CH2:3][CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:6])[CH2:15]1
Reactant: CO[C@@H]1CNCC[C@@H]1NCc1ccccc1
Reactant: O=C(CCCCl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1NCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of 43.9 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine, 55.1 parts of cis-3-methoxy-N-(phenylmethyl)-4-piperidinamine, 37.8 parts of N,N-diethylethanamine and 900 parts of N,N-dimethylformamide was stirred overnight at 70° C. Another portion of 4.4 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine was added and stirring was continued overnight at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of water and sodium carbonate. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 53.1 parts (59.0%) of cis-1-[4-[3-methoxy-4-[(phenylmethyl)amino]-1 piperidinyl]-1-oxobutyl]pyrrolidine as a residue (int. 42).